Towards an NGF-based therapy for Hereditary Sensory and Autonomic Neuropathies IV and V

The rare hereditary sensory and autonomic neuropathies (HSAN) IV and V are linked to defects in Nerve Growth Factor (NGF) signaling which is necessary for survival and function not only of sensory and autonomic neurons, but also for cognitive functions. HSAN IV is clinically characterized by absence of sweating and total lack of reactions to painful stimuli leading to self-mutilation, burn injuries, multiple fractures, and neuropathic joints. It is caused by a rather wide spectrum of mutations in the TrkA gene, encoding for the tyrosine kinase receptor of NGF.Patients affected by HSAN V have a selective congenital loss of pain and temperature sensation leading to painless fractures, bone necrosis, osteochondritis, and neuropathic joint destructions. Sweating is normal. The responsible genetic mutation is in the NGF gene. It is noteworthy that while HSAN IV patients suffer from severe mental retardation, HSAN V patients are cognitively normal. This suggests that neurodevelopmental effects on the clinical phenotype are minor in HSAN V than they are in HSAN IV.While it is known that the HSAN IV mutations decrease the activity of the receptor TrkA, the consequences of the mutation in the NGF gene in HSAN V are less clear. We have recently shown that HSAN V mutated NGF has an altered receptor binding and activation profile, but it is not clear whether the mutation affects the processing of the precursor of human NGF, hproNGF, which is per se endowed of biological activity, or whether the altered pain perception is only due to a decreased signaling of mature NGF. In addition, since no animal models are currently available, no attempt to replace NGF activity and cure the loss of pain perception has been made so far.In this project we plan to understand the role of wild type and mutated hproNGF in physiological pain perception and to create animals models on which we will test the efficacy of a recombinant form of NGF in ameliorating pain perception and cognitive functions.